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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1423175
This article is part of the Research Topic New Drugs and Future Challenges in Drug Metabolism and Transport View all 7 articles

Preclinical Pharmacokinetic Studies and Prediction of Human PK profiles for Deg-AZM, a clinical-stage new Transgelin agonist

Provisionally accepted
Xiaoyu Ai Xiaoyu Ai 1*Xiaoting Gu Xiaoting Gu 1Xiaohe Li Xiaohe Li 1Weixue Tian Weixue Tian 2Chaoyue Zheng Chaoyue Zheng 1Yutian Cai Yutian Cai 1Xiang Xu Xiang Xu 1Conglu Zhao Conglu Zhao 1Hongting Liu Hongting Liu 1Yao Sun Yao Sun 1Zhilin Luo Zhilin Luo 1Shuwen Zhu Shuwen Zhu 1Honggang Zhou Honggang Zhou 1Cheng Yang Cheng Yang 1
  • 1 College of Pharmacy, Nankai University, Tianjin, China
  • 2 The National Institutes of Pharmaceutical R&D Co., Ltd, Beijing, China

The final, formatted version of the article will be published soon.

    Deglycosylated azithromycin (Deg-AZM), a newly developed Class I drug with good therapeutic effects on slow transit constipation, is a small molecule Transgelin agonist which has been approved for clinical trials in 2024. The preclinical pharmacokinetic profile of Deg-AZM was investigated to support the further development for Deg-AZM. The results of plasma protein binding suggested that the plasma protein binding rates of Deg-AZM was lower in mice and rats, higher in dogs, and moderate in humans. By investigating the metabolic stability of liver microsome, it was found that the metabolic process of Deg AZM was similar in rat and human liver microsomes. Pharmacokinetic studies conducted on rats or dogs indicated no significant gender difference in the pharmacokinetic behavior of Deg-AZM. In addition, Deg-AZM was rapidly absorbed into the blood and then quickly eliminated from the body. Plasma exposure of Deg-AZM was dose-dependent with no accumulation after continuous gavage administration. Deg-AZM could widely distributed in the tissues without obvious accumulation. Deg-AZM was mainly excreted from the body through the urinary excretion pathway. Furthermore, the pharmacokinetic profiles in human of Deg-AZM at various doses were predicted based on physiologically-based pharmacokinetic (PBPK) models and we found the pharmacokinetic behavior of Deg-AZM showed dose-dependency. These results could provide valuable information to support the first in-human dosage prediction and phase I clinical design.

    Keywords: 38 Tongyan Road, Jinnan District, Tianjin, P.R.China 300350 Deg-AZM, Nonclinical Pharmacokinetics, Absorption, Distribution, Metabolism, Excretion Deg-AZM, Deglycosylated azithromycin, LC-MS/MS, liquid chromatography coupled with tandem, ESI, electrospray ionization, MRM, multiple reaction monitoring, m/z, mass-to-charge ratio, IS, internal standard, QC, quality control, LLOQ, lower limit of quantification

    Received: 25 Apr 2024; Accepted: 30 Jul 2024.

    Copyright: © 2024 Ai, Gu, Li, Tian, Zheng, Cai, Xu, Zhao, Liu, Sun, Luo, Zhu, Zhou and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Xiaoyu Ai, College of Pharmacy, Nankai University, Tianjin, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.